High Throughput Screening of Medicines for Malaria Ventures Chemical Libraries to Identify Novel Inhibitors of Candida auris

疟疾药物的高通量筛选帮助化学库鉴定新型耳念珠菌抑制剂

• 批准号: 10383652
• 负责人: Jose L. Lopez-Ribot
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-06 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10383652
• 关键词: Academia; Amphotericin B; Antibiotic Resistance; Antifungal Agents; Antifungal Therapy; Awareness; Azoles; Biological; Biological Assay; Candida; Candida albicans; Candida auris; Candidiasis; Cell Line; Centers for Disease Control and Prevention (U.S.); Chronic Disease; Clinic; Clinical; Collection; Data; Development; Disease; Disease Outbreaks; Dose; Epidemic; Etiology; Eukaryota; Fluconazole; Fluconazole resistance; Fungal Drug Resistance; Generations; Growth; Health care facility; Human; Immune; In Vitro; Infection; Laboratories; Libraries; Malaria; Medical; Medical Research; Medicine; Micafungin; Modeling; Modern Medicine; Molds; Multi-Drug Resistance; Mycoses; National Institute of Allergy and Infectious Disease; Nature; Nonprofit Organizations; Nosocomial Infections; Nursing Homes; Parasitology; Patients; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Polyenes; Primary carcinoma of the liver cells; Property; Resistance; Resistance development; Safety; Strategic Planning; Structure; Toxic effect; United States National Institutes of Health; Yeasts; base; combat; design; drug development; emerging pathogen; experimental study; fungus; health care settings; high throughput screening; in vitro activity; in vitro testing; inhibitor; interest; mortality; neglect; novel; novel strategies; novel therapeutics; pathogen; programs; public-private partnership; response; small molecule; small molecule libraries; trend

Candida species represent the most frequent etiological agents of opportunistic fungal invasive infections in an expanding spectrum of immune- and medically-compromised patients, and candidiasis now represents the third-to-fourth most frequent nosocomial infection worldwide, carrying unacceptably high mortality rates of 30-60%, which alarmingly have remained unchanged during the last three decades. Most recently, Candida auris has emerged as a multi-drug resistant opportunistic fungus around the globe, including the U.S, with a notable ability to easily spread between hospitalized patients and nursing home residents leading to major outbreaks in healthcare settings. According to data from the Centers for Disease Control and Prevention (CDC), 90% of C. auris strains in the U.S. have been resistant to fluconazole, 30% have been resistant to amphotericin B, and 5% have been resistant to echinocandins. Thus, the fact that some strains of C. auris demonstrate pan-resistance to all three major classes of clinically-used antifungals agents is particularly concerning. Indeed, in its recently released Antibiotic Resistance Threats in the United States, the CDC has designated C. auris as one of only 5 “Urgent Threats” requiring swift and aggressive action, since there is a grave concern that multi- and pan-resistant C. auris isolates will spread and become prevalent, and mostly untreatable, in the years to come. Thus, there is dire need for the development of novel therapeutics against this emerging pathogen. To conquer this formidable challenge, we propose a highly efficient approach by establishing a novel partnership between academia (our laboratory) and a non-for profit organization (Medicines for Malaria Ventures, MMV) in order to perform high throughput screening (HTS) of MMV’s chemical libraries containing 180,000 small molecule compounds to identify high value compounds with novel antifungal activity against C. auris. Although similar approaches have had a major impact in the Parasitology field, these MMV’s libraries have never before been screened for antifungal activity. To this end, we proposed the following: i) perform HTS of MMV’s chemical libraries to identify high value compounds with novel antifungal activity against C. auris, for which we will use a 384-well microtiter plate based model recently developed in our laboratory to screen MMV’s “Hit-Generation” (140K compounds) and “Diversity” (40K compounds) chemical libraries in order to identify inhibitors of C. auris growth; and ii) to characterize the leading compounds by performing a battery of in vitro tests to further establish their antifungal activity and safety/toxicity properties.

念珠菌属是机会性真菌侵袭性真菌病最常见的病原体 感染的免疫和医疗受损的患者范围不断扩大， 是全球第三至第四大最常见的医院感染，携带令人无法接受的高 死亡率为30- 60%，令人震惊的是，在过去30年中，这一比例没有变化。最 近年来，耳念珠菌已成为地球仪上的一种多重耐药机会性真菌，包括 在美国，这种病毒很容易在住院病人和疗养院居民之间传播， 导致医疗机构的大规模爆发。根据疾病控制中心的数据， 预防（CDC），90%的C。美国的耳菌菌株已对氟康唑产生耐药性，其中30% 对阿替霉素B耐药，5%对棘白菌素耐药。因此，事实上， C.耳表现出对所有三种主要类型的临床使用的抗真菌剂的泛耐药性， 特别是关于。事实上，在其最近发布的《美国抗生素耐药性威胁》中， CDC已指定C。耳炎是需要迅速采取积极行动的仅有的5个“紧急威胁”之一， 人们严重关注多重和泛耐药的C.耳道分离株将传播并流行， 在未来的几年里，大部分都无法治愈因此，迫切需要开发新的治疗方法 对抗这种新出现的病原体为了克服这一艰巨的挑战，我们提出了一种高效的方法， 通过在学术界（我们的实验室）和非营利组织之间建立一种新的伙伴关系， （Medicines for Malaria Ventures，MMV）进行MMV的高通量筛选（HTS）。 包含180，000种小分子化合物的化学库，以识别具有新的 对C.耳。尽管类似的方法在寄生虫学中产生了重大影响， 这些MMV的文库以前从未被筛选过抗真菌活性。为此，我们建议 i）对MMV的化学文库进行HTS，以鉴定具有新的结构的高价值化合物， 对C.耳，我们将使用384孔微量滴定板为基础的模型最近 在我们的实验室开发的筛选MMV的“命中一代”（140 K化合物）和“多样性”（40 K 化合物）化学文库，以鉴定C.耳生长;和ii）表征 通过进行一系列体外试验以进一步确定其抗真菌活性， 安全/毒性特性。

项目成果

High-Throughput Screening of the Repurposing Hub Library to Identify Drugs with Novel Inhibitory Activity against Candida albicans and Candida auris Biofilms.

• DOI: 10.3390/jof9090879
• 发表时间: 2023-08-27
• 期刊: Journal of fungi (Basel, Switzerland)
• 作者: Ajetunmobi OH;Wall G;Vidal Bonifacio B;Martinez Delgado LA;Chaturvedi AK;Najvar LK;Wormley FL Jr;Patterson HP;Wiederhold NP;Patterson TF;Lopez-Ribot JL
• 通讯作者: Lopez-Ribot JL